Abnormally aggregates of the protein tau in the form of neurofibrillary tangles (NFT's) and glial tangles are found in a number of neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism - chromosome 17 type (FTDP-17). For most of these diseases, the role tau plays in disease initiation and progression is not understood. However, for the autosomal-dominant disorder FTDP-17, mutations in MAPT, the gene that encodes tau protein, cause the disease. The clinical and neuropathologic phenotype produced by different MAPT mutations is highly variable. For some mutations, the initial clinical feature is limited to executive function deterioration. For others, severe behavioral disturbances such as disinhibition or psychosis are the initial symptoms. Different neuropathologic phenotypes are observed. For some mutations, aggregated tau is only seen in neurons as NFT's. For others, both neuronal and glial aggregates are found (glial fibdllary tangles, GFT's). The regional distribution of pathology is also varied. In some cases, pathology is seen broadly distributed in the frontotemporal lobes while in other cases, only brain stem regions are involved as seen in progressive supra nuclear palsy (PSP). Two types of FTDP-17 mutations are known. One type is missense mutations that act at the protein level. The second type of mutations, which is the focus of this application, alter the regulation of the alternative splicing of tau exon 10 (El0). Also, susceptibility to PSP is caused by an unidentified allele(s) at a MAPT polymorphic site(s) that influences MAPTsplicing. For FTDP-17 mutations, phenotypic variability is potentially dependent on differential expression patterns of trans-acting splicing regulatory factors in different subpopulations of neurons and glial cells. Differential phosphorylation of trans-acting factors in different cell types may also be involved in phenotypic vadabUity. In this proposal, we will identify the cis-acting sequence elements in tau that affect the regulation of alternative splicing. We will also identify the trans-factors that interact with the cis-acting elements. Identification of c/s-elements may lead to therapeutic approaches based on evolving strategies for manipulating RNA in vivo. Likewise, identification of trans-factors may lead to protein targets such as kinases that are also therapeutic targets.